Mechanism of selective induction of apoptosis in leukemic stem cells by antibodies to EphA3
Acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) are cancers of the blood and bone marrow. AML progresses rapidly and is fatal within months if untreated. Even with aggressive treatment, including chemotherapy and bone marrow transplantation, five-year overall survival rates are less than 40%. The majority of CML cases are managed effectively with tyrosine kinase inhibitors targeting the primary oncogenic protein in this disease, the Bcr-Abl protein. However, disease persistence also remains a problem in CML and the leukemia progresses quickly on cessation of chemotherapy. Current evidence indicates that not all cells in these leukemias are the same, and that there is a rare population of leukemia stem cells (LSC) responsible for maintaining the disease. The LSC are thought to be relatively resistant to current chemotherapies. Thus novel therapies that target the LSC population while sparing the normal blood-forming stem cells in the bone marrow are urgently needed. Such approaches provide the potential for reduced toxicity compared with current chemotherapies and the prospect of ultimately identifying curative therapies.
We have detected a cell-surface protein, termed EphA3, that is present on bone marrow cells isolated from a proportion of AML and CML patients but is not detectable on normal blood-forming cells in the bone marrow or on the blood cells from healthy individuals. EphA3 has been found on different cell types in these leukemias, including cells from AML patients with characteristics of LSCs. A monoclonal antibody to EphA3 is available that, on binding EphA3-expressing cells, directs the cells to undergo cell death (apoptosis). This provides the potential to target LSC selectively using monoclonal-antibody based therapy. The research proposal will explore the effect of anti-EphA3 antibodies on AML-derived cells in cell-based assays of stem cell function including proliferation, self-renewal and the capacity for differentiation into the different tumor cell types. We will also explore the activity of anti-EphA3 antibodies in preventing tumorigenicity of AML-derived bone marrow cells in mouse models of leukemia. Ultimately the results obtained with AML samples will be extended to explore the role of EphA3 in LSC biology in CML and other hematologic malignancies.
There is an urgent need for new treatments for myeloid leukemias. Although the availability of tyrosine kinase inhibitors has contributed significantly to the management of chronic myeloid leukemia (CML), both chronic and acute myeloid lekeumia (AML) remain essentially incurable without allogeneic stem-cell transplantation. Current standard of care for medically fit AML patients typically includes several cycles of high dose chemotherapy. Even with these aggressive treatments, which cause significant morbidity and mortality, relapse is common and the five-year overall survival is 30-40% in adults under the age of 65 and less than 10% in patients over age 65.
Disease persistence in these diseases has been ascribed to the resistance of leukemic stem cells to chemotherapy. Development of curative therapies will require the identification of essential pathways for the survival and self-renewal of leukemic stem cells.We have identified a cell-surface protein, EphA3, present on the leukemic stem cell in a proportion of AML patients but absent from normal blood stem cells. A monoclonal antibody is available that binds to EphA3 and delivers a signal to the EphA3-expressing cell, causing it to undergo cell death (apoptosis). The goals of this proposal are to gain a greater understanding of the biological response of AML leukemic stem cells to monoclonal antibodies targeting EphA3 and to extend the results to other leukemias. There are several benefits of this research for California. The proposed research is intended to support development of a new therapeutic that would offer significant health benefit to residents of our state as well as positively impact our health economics. The project will also contribute directly to the economy of California, by employing individuals who will be essential for the conduct of these studies at a California-based biopharmaceutical company, and through the funding of contract research organizations in California.